Published Online
on February 21, 2005

A more recent version of this article appeared on April 1, 2005

This Article Full Text (PDF) All Versions of this Article: 45/4/545    most recent 01.HYP.0000157409.88971.fcv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsuda, M. Articles by Horiuchi, M. Search for Related Content PubMed PubMed Citation Articles by Tsuda, M. Articles by Horiuchi, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ESTRADIOL Related Collections ACE/Angiotension receptors Pathophysiology

Submitted on December 1, 2004
Revised on January 3, 2005

Inhibitory Effects of AT₁ Receptor Blocker, Olmesartan, and Estrogen on Atherosclerosis Via Anti-Oxidative Stress

Masahiro Tsuda; Masaru Iwai; Jian-Mei Li; Huan-Sheng Li; Li-Juan Min; Ayumi Ide; Midori Okumura; Jun Suzuki; Masaki Mogi; Hiromichi Suzuki; and Masatsugu Horiuchi^*

From the Department of Molecular and Cellular Biology (M.T., M.I., J.-M.L., H.-S.L., L.-J.M., A.I., M.O., J.S., M.M., M.H.), Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shigenobu, Ehime, Japan; and the Department of Nephrology (M.T., H.S.), Saitama Medical School, Moroyama, Saitama, Japan.

^* To whom correspondence should be addressed. E-mail: horiuchi{at}m.ehime-u.ac.jp.

Abstracts--The present study explored the possibility that estrogen enhances the inhibitory effect of an angiotensin II type-1 (AT₁) receptor blocker (ARB), olmesartan, on atherosclerosis, focusing on oxidative stress using apolipoprotein E knockout mice (ApoEKO). After 6 weeks on a high-cholesterol diet, marked atherosclerotic lesion formation with an increase in oxidative stress, such as superoxide production, NAD(P)H oxidase activity and expression of p47^phox mRNA and rac-1 mRNA, were observed in the proximal aorta in both male and female ApoEKO mice, whereas these changes were less marked in female mice. Ovariectomy enhanced these parameters, the changes of which were reversed by 17-estradiol (80 µg/kg per day) replacement. Treatment with olmesartan (3 mg/kg per day) significantly inhibited oxidative stress and atherosclerosis, whereas its inhibitory effects were more marked in female than in male or ovariectomized mice. Smaller doses of olmesartan (0.5 mg/kg per day) or 17-estradiol (20 µg/kg per day) did not influence atherosclerosis and oxidative stress in ovariectomized mice, whereas co-administration of olmesartan and 17-estradiol at these doses attenuated these parameters. An angiotensin-converting enzyme (ACE) inhibitor, temocapril, also inhibited atherosclerotic changes similarly to olmesartan. Moreover, angiotensin II-mediated activation of NAD(P)H oxidase in cultured vascular smooth muscle cells was attenuated by 17-estradiol. These results indicate that estrogen and an ARB synergistically attenuate atherosclerosis at least partly via inhibition of oxidative stress.

Key words: atherosclerosis • estrogen • oxidative stress • receptors, angiotensin II

This article has been cited by other articles:

				L.-Y. C. Wing, Y.-C. Chen, Y.-Y. Shih, J.-C. Cheng, Y.-J. Lin, and M. J. Jiang Effects of Oral Estrogen on Aortic ROS-Generating and -Scavenging Enzymes and Atherosclerosis in apoE-Deficient Mice Experimental Biology and Medicine, September 1, 2009; 234(9): 1037 - 1046. [Abstract] [Full Text] [PDF]

				Y. Ikeda, K.-i. Aihara, S. Yoshida, T. Sato, S. Yagi, T. Iwase, Y. Sumitomo, T. Ise, K. Ishikawa, H. Azuma, et al. Androgen-Androgen Receptor System Protects against Angiotensin II-Induced Vascular Remodeling Endocrinology, June 1, 2009; 150(6): 2857 - 2864. [Abstract] [Full Text] [PDF]

				X. W. Cheng, T. Murohara, M. Kuzuya, H. Izawa, T. Sasaki, K. Obata, K. Nagata, T. Nishizawa, M. Kobayashi, T. Yamada, et al. Superoxide-Dependent Cathepsin Activation Is Associated with Hypertensive Myocardial Remodeling and Represents a Target for Angiotensin II Type 1 Receptor Blocker Treatment Am. J. Pathol., August 1, 2008; 173(2): 358 - 369. [Abstract] [Full Text] [PDF]

				W. J. Welch Angiotensin II-Dependent Superoxide: Effects on Hypertension and Vascular Dysfunction Hypertension, July 1, 2008; 52(1): 51 - 56. [Full Text] [PDF]

				L. Guasti, F. Marino, M. Cosentino, R. C. Maio, E. Rasini, M. Ferrari, L. Castiglioni, C. Klersy, G. Gaudio, A. M. Grandi, et al. Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin II type 1 receptor expression: 1-year follow-up Eur. Heart J., May 1, 2008; 29(9): 1118 - 1126. [Abstract] [Full Text] [PDF]

				S. Hagita, M. Osaka, K. Shimokado, and M. Yoshida Oxidative Stress in Mononuclear Cells Plays a Dominant Role in Their Adhesion to Mouse Femoral Artery After Injury Hypertension, March 1, 2008; 51(3): 797 - 802. [Abstract] [Full Text] [PDF]

				S. Zadelaar, R. Kleemann, L. Verschuren, J. de Vries-Van der Weij, J. van der Hoorn, H. M. Princen, and T. Kooistra Mouse Models for Atherosclerosis and Pharmaceutical Modifiers Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1706 - 1721. [Abstract] [Full Text] [PDF]

				H. Kanamori, G. Takemura, Y. Li, H. Okada, R. Maruyama, T. Aoyama, S. Miyata, M. Esaki, A. Ogino, M. Nakagawa, et al. Inhibition of Fas-associated apoptosis in granulation tissue cells accompanies attenuation of postinfarction left ventricular remodeling by olmesartan Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2184 - H2194. [Abstract] [Full Text] [PDF]

				J. A. Miller, D. Z. Cherney, J. A. Duncan, V. Lai, K. D. Burns, C. R.J. Kennedy, J. Zimpelmann, W. Gao, D. C. Cattran, and J. W. Scholey Gender Differences in the Renal Response to Renin-Angiotensin System Blockade J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2554 - 2560. [Abstract] [Full Text] [PDF]

				S. Kumar, S. Savitz, G. Schlaug, L. Caplan, and M. Selim Antiplatelets, ACE inhibitors, and statins combination reduces stroke severity and tissue at risk Neurology, April 25, 2006; 66(8): 1153 - 1158. [Abstract] [Full Text] [PDF]